As part of the functional relationship which exists between the immune and the neuroendocrine systems, proteins released by activated immune cells, called interleukins (ILs) or cytokines, convey the occurrence of immune stimulation to the hypothalamic-pituitary-adrenal (HPA) axis. The resulting increased activity of the HPA axis induced by ILs is essential to allow the organism to mount proper immune, endocrine and metabolic responses to an antigenic challenge. Consequently, pathological secretory rates of corticotropin-releasing factor (CRF), ACTH and/or corticosteroids during antigenic challenges can result in increased susceptibility immunologic disorders. Alcoholics and children of alcoholic mothers suffer from an increased occurrence of both infectious and inflammatory diseases, conditions that are associated, respectively, with abnormally elevated or blunted activity of the HPA axis. The distribution of these diseases in predisposed individuals indicates a distribution that is skewed by gender. Based on our animal studies, we hypothesize that alcohol-induced changes in the normal response of the HPA axis to immune signals participate in these pathologies, and that the sex steroid milieu influences both the stimulatory effect of cytokines on neuroendocrine functions, and the ability of alcohol to alter these responses. Our studies are therefore aimed at gaining a better understanding of the mechanisms responsible for the ability of alcohol alters the normal functional link between the immune system and the HPA axis. We have shown that exposure to alcohol during embryonic development or postnatally alters the stimulatory effect of ILs on ACTH and corticosterone release. Studies described in the present proposal will extend these results and explore the mechanisms responsible for the influence of alcohol. We will use IL-1beta, endotoxins or a small volume of turpentine to investigate the effect of a single cytokine, of a cascade of cytokines, or of a true inflammatory response, to probe the mechanisms through which alcohol disrupts the response of the HPA axis to immune signals. Under Specific Aim 1, we will study the influence of gender and sex steroids, the role of CRF, vasopressin and their receptors, and of nitric oxide, in mediating the influence of prenatal alcohol exposure on the response of the HPA axis to immune challenges. Under Specific Aim 2, a similar approach will be used to investigate the ability of post-natal alcohol administration to alter the response of the HPA axis of peripubertal and mature rats to cytokines. In both sets of experiments, sophisticated surgical approaches will be combined with techniques of molecular biology to provide a comprehensive investigation of the hypotheses we propose to test. We believe that the concept we present is original, and that the information gained from our studies will form the basis for a novel approach to the treatment of alcohol-related immune dysfunction.